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Mice missing one copy of DDX3X, an autism candidate gene, have smaller brains and worse motor skills than mice with both copies of the gene, according to an unpublished new study.
The researchers presented the results virtually yesterday at the 2021 Society for Neuroscience Global Connectome. (Links to summaries may work only for registered conference participants.)
Mutations in DDX3X cause a syndrome marked by intellectual disability and developmental delays. Because the gene is found on the X chromosome, the disease mainly affects girls. Many people with the syndrome also have autism and other traits, including motor difficulties, anxiety, hyperactivity, and poor muscle tone.
At the 2019 Society for Neuroscience conference, researchers in Silvia De Rubeis’ lab at Icahn’s Mount Sinai School of Medicine in New York City for the first time described a delay in sensory and motor development in a model murine syndrome that has only one functional copy of the gene.
The new findings, presented by Marta Garcia-Forn, postdoctoral researcher in De Rubeis’ laboratory, confirm previous results and deepen the characteristics of the mouse model.
“This is the first developmental, behavioral and whole-brain characterization of a mouse model with constructive validity for DD3X mutations,” Garcia-Forn said.
To assess motor skills, the team measured how long the mice could run on a rotating rod before falling. They also tested the animals’ ability to walk on a balance beam and descend a vertical pole.
Mice missing a copy of DDX3X performed worse on all tests than controls, indicating motor difficulties. The team repeated the tests when the mice were 1 year old and found that these differences became even more pronounced.
Since DDX3X syndrome was first described in 2015, most people known to have it are young. But a woman in her 40s with the disease showed a decline in her motor skills with age, Garcia-Forn says, in line with the team’s findings in mice.
The researchers also gave the mice light shocks, then measured whether they froze – a sign of fear – when they returned to the area where they were shocked. The altered mice froze less often than the controls, indicating that their memory of the event was impaired.
Mice with a single copy of the gene had reduced brain volume on magnetic resonance imaging scans early in life, even adjusting their body size below average. Brain changes were most pronounced in the limbic system, which is involved with emotions, memory, and the olfactory system.
Read more reports from the 2021 Society for Neuroscience Global Connectome.